The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns

T-bet acts as a functional repressor in association with Bcl-6 to antagonize SOCS1, SOCS3, TCF-1, and late-stage IFN-γ to regulate Th1 development

Abasic sites and strand breaks in DNA cause transcriptional mutagenesis in Escherichia coli

DNA damage occurs continuously, and faithful replication and transcription are essential for maintaining cell viability. Cells in nature are not dividing and replicating DNA often; therefore it is important to consider the outcome of RNA polymerase (RNAP) encounters with DNA damage. Base damage in the DNA can affect transcriptional fidelity, leading to production of mutant mRNA and protein in a process termed transcriptional mutagenesis (TM). Abasic (AP) sites and strand breaks are frequently occurring, spontaneous damages that are also base excision repair (BER) intermediates. In vitro studies have demonstrated that these lesions can be bypassed by RNAP; however this has never been assessed in vivo. This study demonstrates that RNAP is capable of bypassing AP sites and strand breaks in Escherichia coli and results in TM through adenine incorporation in nascent mRNA. Elimination of the enzymes that process these lesions further increases TM; however, such mutants can still complete repair by other downstream pathways. These results show that AP sites and strand breaks can result in mutagenic RNAP bypass and have important implications for the biologic endpoints of DNA damage

Inhibition of IL-2 responsiveness by IL-6 is required for the generation of GC-T FH cells

IL-6–mediated inhibition of CD122 allows T FH cells to receive TCR signaling without initiating an inhibitory TCR/IL-2 loop (see the related Focus by Zhou and Yu ).. Unraveling a paradox Germinal center T follicular helper (GC-T FH ) cells are maintained through sustained TCR stimulation, but TCR activation induces IL-2 production and IL-2 receptor expression, which can inhibit T FH cells. Papillion et al. now explore this paradox using an influenza infection model, where they observe that GC-T FH cells can produce large amounts of IL-2 but are relatively unresponsive to this cytokine. Intrinsic IL-6 signaling is required to maintain this state of hyporesponsiveness, which involves a mechanism by which IL-6 prevents STAT5 from associating with Il2rb locus and thereby prevents up-regulation of IL-2Rβ (CD122). This allows GC-T FH cells to tolerate sustained TCR activation without triggering inhibitory IL-2 responses, thus revealing a regulatory mechanism that modulates GC-T FH cell generation (see the related Focus by Zhou and Yu ). Sustained T cell receptor (TCR) stimulation is required for maintaining germinal center T follicular helper (GC-T FH ) cells. Paradoxically, TCR activation induces interleukin-2 receptor (IL-2R) expression and IL-2 production, thereby initiating a feedback loop of IL-2 signaling that normally inhibits T FH cells. It is unclear how GC-T FH cells can receive prolonged TCR signaling without succumbing to the detrimental effects of IL-2. Using an influenza infection model, we show here that GC-T FH cells secreted large amounts of IL-2 but responded poorly to it. To maintain their IL-2 hyporesponsiveness, GC-T FH cells required intrinsic IL-6 signaling. Mechanistically, we found that IL-6 inhibited up-regulation of IL-2Rβ (CD122) by preventing association of STAT5 with the Il2rb locus, thus allowing GC-T FH cells to receive sustained TCR signaling and produce IL-2 without initiating a TCR/IL-2 inhibitory feedback loop. Collectively, our results identify a regulatory mechanism that controls the generation of GC-T FH cells

Additive manufacturing of three-dimensional (3D) microfluidic-based microelectromechanical systems (MEMS) for acoustofluidic applications

Three-dimensional (3D) printing now enables the fabrication of 3D structural electronics and microfluidics. Further, conventional subtractive manufacturing processes for microelectromechanical systems (MEMS) relatively limit device structure to two dimensions and require post-processing steps for interface with microfluidics. Thus, the objective of this work is to create an additive manufacturing approach for fabrication of 3D microfluidic-based MEMS devices that enables 3D configurations of electromechanical systems and simultaneous integration of microfluidics. Here, we demonstrate the ability to fabricate microfluidic-based acoustofluidic devices that contain orthogonal out-of-plane piezoelectric sensors and actuators using additive manufacturing. The devices were fabricated using a microextrusion 3D printing system that contained integrated pick-and-place functionality. Additively assembled materials and components included 3D printed epoxy, polydimethylsiloxane (PDMS), silver nanoparticles, and eutectic gallium–indium as well as robotically embedded piezoelectric chips (lead zirconate titanate (PZT)). Electrical impedance spectroscopy and finite element modeling studies showed the embedded PZT chips exhibited multiple resonant modes of varying mode shape over the 0–20 MHz frequency range. Flow visualization studies using neutrally buoyant particles (diameter = 0.8–70 μm) confirmed the 3D printed devices generated bulk acoustic waves (BAWs) capable of size-selective manipulation, trapping, and separation of suspended particles in droplets and microchannels. Flow visualization studies in a continuous flow format showed suspended particles could be moved toward or away from the walls of microfluidic channels based on selective actuation of in-plane or out-of-plane PZT chips. This work suggests additive manufacturing potentially provides new opportunities for the design and fabrication of acoustofluidic and microfluidic devices

Glacier Change, Concentration, and Elevation Effects in the Karakoram Himalaya, Upper Indus Basin

In recent decades the consequences of climate change for Himalayan glaciers has become of great concern. Glaciers in much of High Asia appear to be declining, some at globally extreme rates (Ageta 2001;Oerlemanns 2001). It had been widely reported that the Indus basin is threatened with severe losses. However, emerging evidence suggests that such reports were, at best, exaggerated (Raina 2009;Armstrong 2010). Several inquiries have concluded that the behavior of Karakoram glaciers differs from those in the rest of the Himalaya and from the more intensively studied European and North American glaciers (Mayewski and Jeschke 1979; Kick 1989; Shroder et al 1993). If so, it suggests conditions exist that distinguish Karakoramglacier environments.Here attention is directed to high-altitude snowfall and nourishment regimes, glacier typology, and “verticality,” especially the role of rockwalls, avalanches, and related conditions above 4000 m elevation—hitherto rather neglected concerns. What can reasonably be deduced about the distribution of terrain and conditions in Karakoram glacier basins from cartographic and satellite imagery is examined as well as how these factors relate to available high-elevation snowfall data. These reveal a distinctive combination of conditions that lead to a strong spatial concentration and intensification of glacier nourishment. They explain and add to the significance of what have been termed “Turkestan”- and “Mustagh”-type glaciers that prevail in the Karakoram. Certain differences emerge, compared with other High Asian mountains, which may explain the seemingly anomalous response to global climate change. However, it is important, first, to be aware of glacier change in the region and that it involves a far from simple picture of advances and retreats: Current knowledge is limited by the fact that most reports are of changes in termini, sometimes ice-tongue thicknesses at their lowest elevations. One must be cautious in inferring what this can tell us about the vast glacier areas up above